Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Mouse, to gestation day 18
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Study was performed to examine developmental toxicity with examination of embryos.
Fertility indices were examined, but dosing did not start until mating.

Data source

Reference
Reference Type:
publication
Title:
Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist 2-18 in mice
Author:
Salim M Bastaki et al
Year:
2017
Bibliographic source:
Dove Press, 19 January 2018 Volume 2018:12 Pages 179—194

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Male and female mice were allowed to mate and following successful mating, females were dosed by intraperitoneal injection.
Treatment continued to Gestation Day 18 and animals examined
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
impurity
Specific details on test material used for the study:
Source Department of Technology and Biotechnology of Drugs (Kraków, Poland)
This is reported as a potential drug for use in as a histamine antagonist
The study was performed on a related polyamide to those substances formed in the reaction process and provides an indicator for possible biological effects.
This type of polyamide is closely related to many types of amine / amide found naturally in plants and animals and has bio-pharmacological effect as a metabolite in normal cells.

Test animals

Species:
mouse
Strain:
other: TO, Harlan Research
Details on test animals and environmental conditions:
Group housed on a 12-h light/dark cycle.
Food and water were available ad libitum.

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
other: Saline
Details on exposure:
Administered at a volume of 1 mL/kg
Doses per animal were 7.5, 15, 30, and 60 mg/kg
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Adult female mice, about 30 g in weight and about 6 weeks of age, were mated with males in the evening, and vaginal plugs identified in the following morning were taken to indicate successful mating.
Plug positive day was regarded as day 0 of gestation
Duration of treatment / exposure:
Treatment took place on days 8 and 13 with termination on Day 18
Duration of test:
To GD 18
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
7.5 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
60 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Approximately 10
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Yes
Ovaries and uterine content:
Yes
Fetal examinations:
Yes; full
Statistics:
Software package SPSS 24.0 (IBM Middle East, Dubai, UAE) was used.
All data were expressed as means ± standard error of mean

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Total number of embryos unchanged between groups
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No difference between groups and controls
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Terminated before full-term
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 60 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
not examined
Description (incidence and severity):
Study terminated prior to birth
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
Description (incidence and severity):
Study terminated prior to birth
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No adverse effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The study was performed on a related polyamide to those substances formed in the reaction process and provides an indicator for possible biological effects.
This type of polyamide is closely related to many types of amine / amide found naturally in plants and animals and has bio-pharmacological effect as a metabolite in normal cells.
There was no indication of reduction in viability of young mice and no evidence of resorptions following IP administration.